This study was conducted to develop formulations of hydrocortisone butyrate (HB)-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) suspended in thermosensitive gel to improve ocular bioavailability of HB for the treatment of bacterial corneal keratitis. PLGA NP with different surfactants such as polyvinyl alcohol (PVA), pluronic F-108, and chitosan were prepared using oil-in-water (O/W) emulsion evaporation technique. NP were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential, and crystallinity.
AAPS PharmSciTech, Vol 17, No 2, April 2016 ( # 2015) DOI: 10.1208/s12249-015-0354-5 Research Article Nanoparticle-Based Topical Ophthalmic Gel Formulation for Sustained Release of Hydrocortisone Butyrate Xiaoyan Yang,1 Hoang M Trinh,1 Vibhuti Agrahari,1 Ye Sheng,1 Dhananjay Pal,1 and Ashim K Mitra1,2 Received April 2015; accepted June 2015; published online 18 June 2015 Abstract This study was conducted to develop formulations of hydrocortisone butyrate (HB)-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) suspended in thermosensitive gel to improve ocular bioavailability of HB for the treatment of bacterial corneal keratitis PLGA NP with different surfactants such as polyvinyl alcohol (PVA), pluronic F-108, and chitosan were prepared using oil-in-water (O/W) emulsion evaporation technique NP were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential, and crystallinity In vitro release of HB from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase Such burst effect was completely eliminated when nanoparticles were suspended in thermosensitive gels and zero-order release kinetics was observed In HCEC cell line, chitosanemulsified NP showed the highest cellular uptake efficiency over PVA- and pluronic-emulsified NP (59.09±6.21%, 55.74±6.26%, and 62.54±3.30%, respectively) after h However, chitosan-emulsified NP indicated significant cytotoxicity of 200 and 500 μg/mL after 48 h, while PVA- and pluronic-emulsified NP exhibited no significant cytotoxicity PLGA NP dispersed in thermosensitive gels can be considered as a promising drug delivery system for the treatment of anterior eye diseases KEY WORDS: hydrocortisone butyrate; PLGA nanoparticles; thermosensitive gel; topical administration INTRODUCTION Eye drops are generally formulated as aqueous solutions Rapid tear turnover, hydrophobic structure of the corneal epithelium, and lachrymal drainage can lower ocular bioavailability to less than 1% [1] Moreover, a major proportion of a dose (about 90% of the instilled drug) cannot permeate through the cornea A small fraction of the dose is absorbed into the systemic circulation by the conjunctival and nasal blood vessels, causing secondary effects [2] Topical corticosteroids are administered by drops, suspension, creams, and ointment for ocular inflammation A 0.1% hydrocortisone butyrate (HB) ointment displayed no eye irritation in rabbits [3, 4] However, a conventional ophthalmic formulation of steroids may only achieve short-term relief of inflammation, owing to very limited residence in the precorneal area Therefore, steroids require frequent administrations, leading to side effects Lipophilic HB for the treatment of inflammation suffers from poor solubility, low bioavailability, and severe side effects A few attempts to increasing dissolution and bioavailability of HB have met with limited success [5–8] Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, USA To whom correspondence should be addressed (e-mail: mitraa@umkc.edu) 1530-9932/16/0200-0294/0 # 2015 American Association of Pharmaceutical Scientists Over the last decade, biodegradable nanoparticles (NP) have been developed to regulate drug release, increase accessibility to specific tissue compartments, modulate biodistribution, and enhance bioavailability of poorly soluble drugs [9, 10] Polymeric NP have been considered as the most promising system for ocular drug delivery [11, 12] Owing to its excellent biocompatibility, biodegradability, and mechanical strength, poly(D,L-lactide-co-glycolide) (PLGA) has been employed for the delivery of therapeutic agents [13] It was selected as a matrix to prepare small NP with size